System to Measure Blood Coagulation Related Parameters

ABSTRACT

System to measure blood coagulation related parameters comprising one first channel ( 6 ) adapted to contain a blood sample; said system containing, at least partially, an expandable material which is able to increase its volume when activated by an exciting source; said system furthermore comprising several excitable regions distributed close to said first channel ( 6 ), in such a way that, when one of said excitable region is activated, said expandable material increases to such an extend that the channel cross section is reduced to a location situated at or near to said excitable region.

FIELD OF INVENTION

The invention relates to portable devices and methods for measuring coagulation time, such as for example prothrombin time or activated partial thromboplastine time.

STATE OF THE ART

In case of atrial fibrillation, deep venous thrombosis, pulmonary embolism or after replacement of cardiac valve, taking medication is necessary to maintain normal blood fluidity. The most commonly used drugs are heparin and warfarin. Heparin is administrated subcutaneously or intravenously. Heparin activates a plasmatic protein, the antithrombin III that is a natural inhibitor of protease implicated in the coagulation cascade (factors VIIa, XIa, IXa, Xa, IIa). The rate of inactivation of these proteases by AT-III increases 1000-fold due to the binding of heparin. Warfarin decrease blood coagulation by interfering with vitamin K metabolism by inhibiting the effective synthesis of biologically active forms of the Vitamin-K-dependent clotting factors II, VII, IX and X, as well as the regulatory factors protein C, protein S and protein Z. Warfarin has the advantage that it may be taken orally. However dosing warfarin is complicated by the fact that it is known to interact with many commonly used medications and other chemicals that may be present in appreciable quantities in food. But with both medications, dangerous side effects such as bleeding exist. Therefore in order to optimize the therapeutic effect and minimize risks for the patient, close monitoring of the degree of anticoagulation is required by blood testing. Two coagulation test measures are routinely used: the prothrombin time and the activated partial thromboplastin time. Both tests measure clotting time to evaluate a patient's baseline haemostatic state or to monitor the response to anticoagulant therapy as well as the overall function and status of the coagulant system. Prothrombin time is tested when warfarin is used and activated partial thromboplastin time when heparin is used. These tests are mainly done in hospital with relatively large laboratory instrument of complex technology and therefore must be done by qualified personnel. These types of tests are expensive and can be done only once a month approximately. Another possibility is to use point-of-care device. In this case the patient can perform the test by himself. This allows a better control over time as the test can be done daily. However, even if it has been shown self-management improves the quality of oral anticoagulation [1], this method is little used. This is mainly due to the cost of the test strips and to the complexity of use of the actual devices. Therefore new easy of use and inexpensive point-of-care devices and methods for blood coagulation testing are needed.

Methods for coagulation measurement using portable device are described in the following patents

-   -   U.S. Pat. No. 5,908,786: measurement of blood displacement using         liquid crystal and heat     -   U.S. Pat. No. 6,673,622 BI: measurement of change in impedance     -   WO 2005/114140: measurement of blood displacement using magnetic         beads     -   U.S. Pat. No. 5,302,348: measurement of blood displacement         speed.     -   U.S. Pat. No. 4,964,728: measurement of blood turbidity by         optical means     -   US 2005/0233466: measurement of blood viscosity using         ferromagnetic agitator

REFERENCE

-   [1] C. Heneghan, Self-monitoring of oral anticoagulation: a     systematic review and meta-analysis, Lancet 2006, 367:404-11

GENERAL DESCRIPTION OF THE INVENTION

The present invention simultaneously concerns an alternative and an improvement with respect to state-of-the-art coagulometers.

To this effect it relates to a system to measure blood coagulation related parameters comprising one first channel adapted to contain a blood sample, the system containing, at least partially, an expandable material which is able to increase its volume when activated by an exciting source, said system furthermore comprising several excitable regions distributed close to said first channel, in such a way that, when one of said excitable region is activated, said expandable material increases to such an extend that the channel cross section is reduced at a location situated at or near to said excitable region.

Preferred embodiments of the system according to the invention are defined in the dependent claims.

The invention furthermore relates to the use of a system to measure blood coagulation related parameters as defined above. Wherein the coagulation time is based on the distance made by the liquid along the channel before being stopped, said liquid being moved by a sequential activation of the exciting elements.

The inventive concept is based on the measurement of the displacement of blood along a channel. The displacement is driven by the closing of a channel located in a material that can change its volume when activated by an exciting factor. The device includes a permanent and a disposable part. The disposable part is in contact with blood and contains the channel in which the blood will move. The permanent part contains an electronic that will trigger the activation of the material and measure the displacement. It also contains a screen to read the result of the test. In the rest of this document, expansible material will be described as PDMSXB, i.e. Expancel beads dispersed into a PDMS matrix, and activation mean as heat produced by the resistance of an electric circuit. Naturally this description can apply to any material having the property to change its volume when activated by an exciting factor.

DETAILED DESCRIPTION OF THE INVENTION

The invention will be better understood below with an example illustrated by the following figures:

FIG. 1 is an illustration of the entire device (permanent +disposable part)

FIG. 2 is a side view of disposable part with the channel molded in the PDMS layer

FIG. 3 is a side view of disposable part with the channel molded in the PDMSXB layer

FIG. 4 is a top view of the disposable part FIG. 5 is a detailed view of a resistance

FIG. 6 is an illustration of the functioning of the device from a front view

FIG. 7 is an illustration of the functioning of the device from a side view

FIG. 8 is an illustration of the functioning of the device with a non miscible fluid pushing the blood, from a side view

The following numerical references are used in the figures

-   -   1. PCB     -   2. PDMS layer     -   3. PDMSXB layer     -   4. protective layer     -   5. coverlayer     -   6. channel     -   7. inlet hole     -   8. outlet hole     -   9. resistance     -   10. region of narrowing     -   11. permanent part     -   12. disposable part     -   13. measurement window     -   14. screen for result reading     -   15. blood     -   16. non miscible fluid

The disposable part 12 is formed by the superposition of the following layers: a PCB layer 1, a PDMS layer 2, a PDMSXB layer 4, a protective layer 4 and a cover layer 5. The resistances 9 producing heat to activate the material are printed on the PCBlayer 1. The channel network in which the blood is displaced is molded in the POMS or in the PDMSXB layer. The protective layer is preferably biocompatible with blood and/or ensure thermal isolation of the blood against the heated material. The protective layer can consist of the superposition of two layers, one ensuring thermal isolation and the other biocompatibility. The protective layer covering the PDMS and the one covering the PDMSXB are not necessarily the same. The cover layer closes the channel but preferably contain an inlet hole that connect the channel to the outside in order to let the blood enter the device and an outlet hole The disposable part is preferably adapted to the sensing mean incorporated to the permanent part, for example, if optical mean is used, the disposable is preferably transparent to the light used by, for example, containing a window.

The channel network preferably has the following properties:

-   -   The channel network contains at least two identical channels to         be able to perform the coagulation test and a control test in         the same time (FIG. 4).     -   Each small channel in the network is able to contain chemical         species necessary for the test to be performed and allow them to         be mixed with blood.     -   Each small channel in the network contains a narrowing allowing         to stop the blood entering the device and therefore to control         the volume of blood displaced in each channel (FIG. 4)

The channel network may also have the following properties:

-   -   Each small channel may contain several narrowing to stop the         blood.     -   The chemical species necessary for the test to be performed are         contained in reservoirs linked to the channel network

The resistance printed on the PCB preferably has the following properties:

-   -   Under each channel a first resistance is placed upstream of the         narrowing. The size of this resistance determines the volume of         blood that will be displaced in the channel.     -   Downstream of the narrowing, identical resistance are placed in         series along a channel and in parallel along the different         channels.     -   Each resistance consists in a folded line. The foldings are more         and more distant along the resistance to allow a progressive         heating and therefore a progressive closing of the channel (FIG.         5).

Description of the functioning: sample of blood is taken from the patient, for example with a lancet. The sample is placed on the cover hole and is aspired inside the device by capillary forces or by a pumping mechanism (FIGS. 6.b & 7.a). The sample of blood fills the different channel until their narrowing where it is stopped due to change in fluidic resistance. At this stage, it may be mixed with chemical reactive needed to perform the test. The resistances placed upstream the narrowing are heated and this part of the channels is progressively closed and a volume of blood corresponding to the size of the resistance is push forward in the channel (FIGS. 6.c & 7.b). This allows controlling the volume of blood to be analyzed. The resistances are then heated one after the other along a channel, with a controlled amount of time between each successive heating (FIGS. 6.d-e & 7.c). The resistances are heated simultaneously along the different channels, in order to compare the coagulation time in the different channel, i.e. the coagulation time of blood mixed with different chemical. As long as blood has not coagulated, it may be push forward by the closing of the channel, but once coagulated it stays in place and the channel may not be closed (FIGS. 6.f & 7.d). Coagulation time is calculated by determining, for example optically, where the clot stays and at what time the corresponding resistance was heated.

In order to avoid direct contact of the blood with the activated region, another fluid that is non miscible with blood may be placed upstream of the blood in the channel. This other fluid is therefore the one that is displaced by the closing of the channel, and its displacement induces blood displacement (FIG. 8).

Of course the present invention is not limited to the embodiments discussed above. 

1. System to measure blood coagulation related parameters comprising one first channel adapted to contain a blood sample; said system containing, at least partially, an expandable material which is able to increase its volume when activated by an exciting source; said system furthermore comprising several excitable regions distributed close to said first channel, in such a way that, when one of said excitable region is activated, said expandable material increases to such an extend that the channel cross section is reduced at a location situated at or near to said excitable region.
 2. System according to claim 1 furthermore comprising at least a second channel, said second channel being parallel to and communication at one of its end with said first channel.
 3. System according to claim 1 wherein said material is adapted to be activated by heat, light, pH variation or by a chemical, electromagnetic or radioactive element as exciting factor.
 4. System according to claim 1 wherein said material is a mixture comprising Expancel®.
 5. System according to claim 1 in combination with an exciting source, such as a laser, which is distinct from said system.
 6. System according to claim 1 furthermore comprising an exciting source such as an electrical resistance.
 7. System according to claim 1 wherein said channel is defined by two horizontal and two lateral walls.
 8. System according to claim 7 wherein at least one of said horizontal walls is made of said expandable material.
 9. System according to claim 1 wherein said channel cross section is adapted to be reduced along a vertical direction.
 10. System according to claim 7 wherein both lateral walls are made of said expandable material.
 11. System according to claim 10 wherein said channel cross section is adapted to be reduced along a horizontal direction.
 12. System according to claim 1 wherein the said material is expandable and is a mixture comprising PDMS or a biocompatible material.
 13. System according to claim 1 wherein said channel(s) comprise(s) at least a region of narrowing.
 14. System according to claim 1, said system having a multilayered structure comprising successively a substrate layer, an expandable layer, a rigid layer and a cover layer, said substrate layer incorporating said exciting source and said channel(s) being defined in said rigid layer.
 15. System according to claim 14 wherein said substrate layer is made of PCB, said expandable layer is made of PDMSXB et said rigid layer is made of PDMS.
 16. System according to claim 1 furthermore comprising sensing means.
 17. System according to claim 16 wherein said sensing means are diodes, optical density or impedance measuring means.
 18. System according to claim 16 wherein said sensing means are adapted to locate where the blood stops.
 19. System according to claim 16 wherein said sensing means are adapted to detect blood displacement.
 20. Assembly comprising a system as defined in claim 1 in combination with at least one reservoir communicating with said channel(s), said reservoir(s) being adapted to contain reactive which are used in the coagulation tests.
 21. Use of a system or an assembly as defined in claim 1 for determining the coagulation time based on the distance made by the liquid along the channel before being stopped, said liquid being moved by a sequential activation of said exciting sources.
 22. Use of a multi-channel system or an assembly as defined in claim 1 wherein each channel is used for a test.
 23. Use according claim 22 wherein all channels are used for carrying out the same test.
 24. Use of a system or an assembly as defined in claim 1 characterized by the use of a pushing fluid which is non miscible with blood and located between blood and the region of the channel being closed. 